Oral Treprostinil is Associated with Improved Survival in FREEDOM-EV and its Open-Label Extension.

INTRODUCTION: In the event-driven FREEDOM-EV trial, oral treprostinil delayed clinical worsening in patients with pulmonary arterial hypertension (PAH). Open-label extension studies offer additional data about tolerability, efficacy, and survival, especially for those initially assigned placebo. The aim of the current study was to determine if oral treprostinil changed survival when considering the parent and extension study, if treprostinil provides functional benefits for participants initially assigned to placebo, and if the benefits observed for those treated with treprostinil were durable. METHODS: Both active and placebo participants from FREEDOM-EV could enroll in the FREEDOM-EV open-label extension (OLE) study after experiencing an investigator-assessed clinical worsening event or after parent study closure. All participants in the OLE were offered open-label oral treprostinil. Previously assigned placebo participants titrated to maximally tolerated doses; previously assigned treprostinil participants continued dose titration. We repeated assessments including functional class and 6-min walk distance (6MWD) at 12-week intervals and measured N-terminal pro-brain natriuretic peptide (NT-proBNP) at week 48. Survival was estimated by Kaplan-Meier analysis, and we estimated hazard ratio (HR) using Cox proportional hazards. RESULTS: Of 690 FREEDOM-EV participants, 470 enrolled in the OLE; vital status was available for 89% of initial Freedom-EV participants. When considering the combined parent and open-label data, initial assignment to oral treprostinil reduced mortality (HR 0.64, 95% confidence interval 0.46-0.91, p = 0.013); absolute risk reduction was 9%. Participants randomized to placebo who initiated oral treprostinil after clinical worsening and tolerated treatment through week 48 demonstrated favorable shifts in functional class (p < 0.0001), 6MWD improvements of + 84 m (p < 0.0001), and a reduction in NT-proBNP of - 778 pg/mL (p = 0.02), compared to OLE baseline. Modest trends toward benefit were measured for those initially assigned placebo who did not have clinical worsening, and 132/144 (92%) of treprostinil assigned participants without clinical worsening remained on drug at week 48 in the OLE study. Adverse events were consistent with FREEDOM-EV. CONCLUSION: Initial treprostinil assignment improved survival in the entire data set; those who began treprostinil after a clinical worsening in the placebo arm and tolerated drug to week 48 enjoyed substantial functional gains. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01560637.

Identification of Chinese Hospitalized Patients' Risk Profile for Venous Thromboembolism (DissolVE1): A Study Protocol of a Non-Interventional Registry Study.

INTRODUCTION: Venous thromboembolism (VTE) is a frequent cause of hospitalization, mortality, and long-term adverse consequence among medical and surgical inpatients. The current study is performed to identify the prophylaxis of patients with VTE risk within the 6 weeks prior to the diagnosis of VTE, and the treatment pattern during 3 months after VTE diagnosis in Chinese patients hospitalized for surgeries or medical illness. METHODS: This multicenter, non-interventional, observational registry plans to enroll 1200 patients from 40 centers in China. The study will retrospectively collect data from patients' hospitalization record within 6 weeks of VTE diagnosis and prospectively follow-up patients for 3 months (in four visits). The primary outcome is to determine the percentage of patients receiving adequate prophylaxis in patients hospitalized within 6 weeks before VTE diagnosis and treatment pattern within 3 months after VTE diagnosis. Important secondary endpoints include determining patients with risk of VTE in the hospital setting, risk factors for VTE, and cost analysis of VTE treatment. EXPECTED OUTCOMES: The findings will determine the characteristics of VTE, its treatment practices, cost of treatment, and quality of life in patients; this information may help in building diagnostic and prophylaxis strategies for VTE in China. TRIAL REGISTRATION: The study is registered in the Venous Thromboembolism Registry in China with study number DIREGL07581. FUNDING: Sanofi China.

Effect of recombinant single-chain urokinase-type plasminogen activator on experimental pulmonary embolism.

UNLABELLED: To compare experimental canine pulmonary thromboembolism (PTE) treatment effects among domestic recombinant single-chain urokinase-type plasminogen activator (scu-PA), recombinant tissue plasminogen activator (rt-PA), and heparin, we injected autologous blood clots into 19 dogs. Those dogs were divided into 3 groups randomly: (1) scu-PA group (n = 6), (2) rt-PA group (n = 6), and (3) heparin group (n = 7). The measurement of hemodynamics and pulmonary angiography was, respectively, carried out at the time spots of preemboli and postemboli, 2 hours and 3 hours after treatment. RESULTS: (1) An obvious increase in mean pulmonary arterial pressure (mPAP) from preemboli (P < .01) and a decrease in cardiac output (CO; P < .01) after blood clot injection. (2) Intergroup comparisons 2 and 3 hours after treatment: mPAP in scu-PA and rt-PA groups were remarkably lower than those of heparin group (P < .05). (3) Intragroup comparisons after thrombolysis, mPAP declined obviously (P < .01), heparin group saw a further decrease in CO. (4) Pulmonary angiography scoring: decrease in the 2 thrombolytic groups was higher than that of the heparin group. CONCLUSIONS: The effects of domestic recombinant scu-PA in experimental PTE resemble that of rt-PA in terms of the improvements of hemodynamics and angiography, better than heparin.